Ichthyosis
There are several known genetic diseases of the skin. For example, defects in the gene encoding steroid sulphatase are associated with X-linked ichthyosis, defects in K1 and K10 keratin genes are linked to epidermolytic hyperkeratosis and defects in the gene encoding transglutaminase I are associated with lamellar ichthyosis (Epstein, 1996; Williams, 1992). Ichthyosis vulgaris, on the other hand, has no known molecular defect.
Ichthyosis vulgaris is an autosomal dominant genetic and acquired skin disorder affecting about 1/300 individuals. Characteristics of ichthyosis vulgaris include a scaly "fish-skin" appearance with abnormal desquamation, epidermal hyperproliferation, lack of production of keratohyalin granules, and hyperkeratosis, exemplified by the cornified layer containing an excess of incompletely differentiated corneocytes and a defective barrier function. There is currently a need in the industry for models of ichthyosis vulgaris, including animal models, to enable screening and identification of compounds for the treatment of this disease.
MDM2
The MDM2 (murine double minute 2) gene was originally discovered as an oncogene that is amplified in the spontaneously transformed BALB/c 3T3DM cell line (Cahilly-Snyder et al., 1987; Fakharzadeh et al., 1991). MDM2 over-expression was subsequently implicated in the pathogenesis of human neoplasia via inhibition of the p53 tumor-suppressor protein (Chen et al, 1996; Cordon-cardo et al., 1993; Finlay, 1993; Haines at al., 1994; Haupt et al., 1996; Leach et al;, 1993, Momand et al, 1992; Oliner et al. 1992; Oliner et al., 1993; Wu et al., 1993). Specifically, the MDM2 gene was found to encode a 90 kD protein capable of forming a complex with p53, inhibiting the tumor surpressor protein's ability to activate transcription and induce apoptosis (Barak et al., 1992; Chen et al., 1993; Finlay, 1993; Haines et al., 1994; Haupt et al., 1996; Momand et al, 1992; Oliner et al., 1993; Wu et al., 1993).
The human MDM2 gene (hMDM2) has been found to be amplified or overexpressed in a significant number of human tumors containing wild type p53 (Oliner et al. 1992; Cordon-cardo et al., 1993; Leach et al, 1993). Negative regulation of p53 by MDM2 has been shown to be essential during mouse development since MDM2 null mice exibit embryonic lethality shortly after implantation but MDM2/p53 double knock out mice are viable (Montes de Luca et al., 1995; Jones et al., 1995). However, there are several indications that inhibition of p53 activity is not the only function of MDM2. In particular, MDM2 can transform cells in the absence of p53 (DubsPottersman et al, 1995). Sigalas et al. (1996) showed that alternatively spliced forms of MDM2 that lack p53 binding domain are able to transform NIH3T3 cells and are found more frequently in poorly differentiated tumors. MDM2 inhibits MyoD function, resulting in a dominant non-differentiating phenotype in muscle (Fiddler et al., 1996).
MDM2 is expressed in skin and appears to be particularly important in skin function. MDM2 is also expressed in respiratory epithelium during mouse development, suggesting that it may have an important role in other epithelia. Preliminary evidence indicates that MDM2 is predominantly expressed in the basal layer, where the amounts decrease upon differentiation. This suggests that MDM2 is involved in cell division in the basal layer, and that the hyperproliferative defect of ichthyosis is treatable by decreasing MDM2 levels. There are, however, no current models for studying ichthyosis, or for screening potential therapeutic compounds for this disease. The present invention overcomes these problems.